Abstract
Brain pericytes are unique, multi-functional mural cells located at the center of the NVU. Pericytes maintain the blood-brain barrier (BBB), promote vascular stability, and control the capillary blood flow. We have previously shown that diabetes alters the functions of the pericytes causing BBB damage and increased cerebrovascular pathological neovascularization. GLP-1 agonists, used in the management of diabetes, showed vascular protective effects. However, the underlying mechanisms are unclear. We hypothesis that GLP-1 receptor nitration contributes to the loss of pericytes functions in diabetes. Methods: Expression of GLP-1R in pericytes was assessed in the brain of control and diabetic mice and human brain microvascular pericytes using IHC, RT-PCR, and Western blots. BBB was assessed using Western blot/IHC of Occludin, VEGF, and MMPs gelatinase. Vascular integrity was determined by measuring cerebrovascular neovascularization indices (vascular density, tortuosity, and branching density). GLP-1R nitration was determined by immunoprecipitation and slot blotting. Results: In the present study, we provide novel evidence that the human brain pericytes express the GLP-1R (P<0.05). Moreover, diabetes increased GLP-1R expression in pericytes (P<0.05). Diabetes caused BBB dysfunction, loss of cerebrovascular integrity, and increased all pathological neovascularization indices (P<0.05). Diabetes increased nitration of GLP-1R. Treatment of pericytes with Exendin-4, a GLP-1 agonist, under diabetic conditions, decreased diabetes-induced inflammation, oxidative stress, and pericytes migration, which ameliorated the integrity of the BBB, and prevented the pathological neovascularization (P<0.05). Conclusion: Our results provide novel evidence that pericytes express GLP-1R and that diabetes increased receptor expression and nitration. Treatment of pericytes with GLP-1R agonist exerts neurovascular protective effects, making it a promising strategy in preventing diabetes- mediated cerebrovascular microangiopathy.
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